The present invention relates to a process for producing soluble and insoluble copolymers of cyclodextrin(s) and/or cyclodextrin derivative(s) and polycarboxylic acid(s), and to soluble copolymers of cyclodextrin(s) and/or cyclodextrin derivative(s) and polycarboxylic acid(s).
Cyclodextrins are cyclic oligomers composed of 6, 7 or 8 glucose units respectively termed xcex1, xcex2 and xcex3 cyclodextrin. The structure of the cyclodextrin molecule can be compared to a truncated cone the external portion of which has hydrophilic properties, while the interior forms a hydrophobic cavity that is capable of reversibly forming inclusion complexes with certain molecules of a hydrophobic nature. Due to that molecular structure, cyclodextrins have long been known to be molecules that are capable of reversibly trapping certain substrates of a hydrophobic nature, in particular aliphatic or aromatic molecules, from their solutions, vapors or solid mixtures. Cyclodextrin-substrate complexes are known as supramolecules or inclusion complexes.
A major disadvantage of cyclodextrins in their unrefined form is their relatively small size, which makes them difficult to extract from solutions, in particular using conventional membrane techniques. Further, their complexing properties and release properties may be limited by their low solubility, in particular in the case of xcex2-cyclodextrin.
Cyclodextrin polymers, on the other hand, enjoy a number of advantages. Since they are much larger than cyclodextrins, they can be separated more easily from liquid media. An insoluble cyclodextrin polymer, for example, can be separated by filtration, and a soluble cyclodextrin polymer, for example, can be isolated by ultrafiltration or using any membrane technique.
The macromolecular structure of cyclodextrin polymers means that they can be considered to be polymeric materials.
The other advantage of cyclodextrin polymers is that the stability constants of the polymer-substrate complexes are often higher than those of cyclodextrin-substrate complexes. As a result, hydrophobic compounds and hydrophilic compounds are more readily complexed and less readily liberated by cyclodextrin polymers than by the cyclodextrins themselves. This property is particularly important for hydrophilic compounds that are not complexed, or are slightly complexed by cyclodextrins in their unrefined form.
Known cyclodextrin polymers can be soluble or insoluble in water depending on their structure.
Insoluble cyclodextrin polymers, for example, are used as separation materials in different chromatographic techniques, materials for absorbing undesirable substances or with high added value, or as a reservoir for active substances, for example drugs, pesticides, insecticides or the like, with a view to controlled release.
Soluble cyclodextrin polymers also have a wide range of applications. As an example, they possess good catalytic properties in esterolysis reactions and can enable controlled release of a substance through a membrane, or they can separate organic compounds from two-phase systems.
Three types of cyclodextrin polymer exist.
In the first polymer type, the cyclodextrin is not bonded to the polymer by a covalent bond. This is the case when the cyclodextrin forms a complex with the macromolecular chain of a polymer to form a necklace-like complex, termed a polyrotaxan, when the cyclodextrin forms an inclusion complex with hydrophobic side chains of a polymer (lateral polyrotaxan), or when the cyclodextrin is physically incorporated by simple mixing with a polymer.
In the next two polymer types, the cyclodextrin is covalently bonded to the polymer, either in the polymer backbone or as a substituent on the polymer chain. In both cases, polymer solubility depends on the molar mass of the polymer and on its degree of polymerization.
Methods for synthesizing cyclodextrin polymers, wherein cyclodextrin itself constitutes the backbone, frequently result in the simultaneous production of soluble and insoluble polymers; the soluble polymer/insoluble polymer weight ratio changes with the reaction parameters.
Such methods are based on the use of different bifunctional agents such as epichlorhydrin, dialdehydes, dibasic acids, diesters, dibasic acid dichlorides, diepoxides, diisocyanates or dihalogenated derivatives, polyisocyanates, ethylene glycol bis(epoxypropyl)ether, dibasic carboxylic acid dihalides in an organic solvent, , or phytic acid.
A process for producing cyclodextrin copolymers using epichlorhydrin has been proposed by Nestlxc3xa9 (NETH 6505361) and by Solms and Egli (Helv. Chim. Acta 48, 1225 (1965); U.S. Pat. No. 3,420,788). Similarly, a number of modifications to the epichlorhydrin cross-linking method were also proposed in documents GB 1 244 990, Wiedenhof N. et al., Die Stxc3xa4rke 21(5), 119-123 (1969), Hoffman J. L., J. Macromol. Sci-Chem., A7(5), 1147-1157 (1973), and in Japanese patents JP-A-58171404 and JP 61283601.
A process using a dialdehyde, a dibasic acid, a diester, a dibasic acid dichloride, a diepoxide, a diisocyanate or a dihalogenated derivative has been described in U.S. Pat. No. 3,472,835. This method proposes activating cyclodextrins by the action of metallic sodium in liquid ammonia followed by reaction with the bifunctional cross-linking agent.
A process using polyisocyanates in organic aprotic solvents has been disclosed in U.S. Pat. No. 4,917,956, Asanuma H. et al., Chem. Commun., 1971-1972 (1997) and in International patent WO-A-98 22197.
A process using ethylene glycol bis(epoxypropyl) ether was disclosed by Fenyvesi E., et al., in the document Ann. Univ. Sci. Budapest, Rolando Eotvos Nominatae, Sect. Chim. 15, 13-22 (1979). A process using other diepoxy compounds has also been described by Sugiura I., et al., in the document Bull. Chem. Soc. Jpn., (62, 1643-1651 (1989)).
A process using dibasic carboxylic acid dihalides in an organic solvent was developed in U.S. Pat. No. 4,958,015 and U.S. Pat. No. 4,902,788.
A process based on phytic acid, a polyphosphoric acid used to cross-link cyclodextrin by a vacuum heat treatment, has been described in U.S. Pat. No. 5,734,031.
In European patent EP-A-0 502 194, Yoshinaga proposed synthesizing cyclodextrin polymers of different natures such as polyurethane, polyurea, unsaturated polyesters, polyesters, polycarbonates, polyamides and polysulphones. Such polymers are obtained by a particular method that encourages the production of linear polymers, since only two of the alcohol functions react with the co-monomers. Such polymers, which contain no carboxylic acid functions, are intended to form degradable membranes with complexing properties.
A second type of polymer, where the cyclodextrin is a pendent group from a polymer chain, is produced by grafting cyclodextrin(s) or cyclodextrin derivative(s) to a pre-existing polymer chain. Halotriazine and halopyrimidine derivatives of cyclodextrins have been synthesized. Cyclodextrin grafting was carried out by reacting those derivatives with cellulose substances as described in German patent DE 19520989. Further, cyclodextrins have also been functionalized with aldehyde groups then grafted onto chitosan by a reductive amination reaction; such a reaction has been described by Tomoya T., et al., in J. Polym. Sci., Part A: Polym. Chem., 36 (11), 1965-1968 (1998).
Those cyclodextrin-based polymers can also be synthesized by functionalization thereof by polymerizable functional groups such as acryloyl or methacryloyl groups. Such functionalization is followed by polymerization or copolymerization of those derivatives. Such processes have been described in DE-A-4 009 825, by Wimmer T., et al., in Minutes Int. Symp. Cyclodextrins, 6th 106-109, (1992), Ed: Hedges A. L., pub. Sante Paris, by Harada et al., in Macromolecules 9(5), 701-704, (1976) and by Janus L. et al., in Reactive and Functional Polymers (in press).
Finally, a process using acrylates, acrylic acid and styrene, rendering the cyclodextrin insoluble by emulsion polymerization, has been described in EP-A-0 780 401.
The principal disadvantage of processes for cross-linking cyclodextrin with epichlorhydrin is that the latter reactant is corrosive and toxic. Similarly, processes based on the use of diepoxy compounds have proved to be toxic and expensive. Cross-linking with polyisocyanates and dibasic acid dihalides requires the use of organic solvents that are not environmentally friendly and thus cannot be used on a large scale. The approach consisting of transforming cyclodextrins into reactive derivatives that can react with polymers is also laborious and expensive.
Currently, the only non polluting method using cheap reactants is that described by Billy D. C. et al., in Proc. Int. Symp. Controlled Release Bioact. Mater. 24th, 545-546 (1997). In that method, mixing poly(acrylic) acid with cyclodextrin in olive oil produces microspheres of insoluble cyclodextrin polymer complexed with oleic acid from the olive oil. However, that method cannot produce the insoluble polymer alone, i.e., not complexed with oleic acid. Further, the substantial reaction time (3 hours) and the way the process is implemented mean that it is not economical for use on an industrial scale.
The present invention proposes a non polluting, cheap process for producing polymers based on cyclodextrin(s), which can be used on an industrial scale.
The process for producing soluble and insoluble polymers based on cyclodextrin(s) and/or cyclodextrin derivative(s) and/or inclusion complex(es) of cyclodextrin(s) and/or cyclodextrin derivative(s) is characterized by the following operations:
preparing a solid state mixture of cyclodextrin(s) and/or cyclodextrin derivative(s) and/or inclusion complex(es) of cyclodextrin(s) and/or cyclodextrin derivative(s) and a poly(carboxylic) acid and/or a poly(carboxylic) acid anhydride or a mixture of poly(carboxylic) acid(s) and/or poly(carboxylic) acid anhydride(s), and optionally, a catalyst;
heating the solid mixture to a temperature in the range 100xc2x0 C. to 200xc2x0 C. for a period in the range 1 minute (min) to 60 min, preferably 30 min or substantially 30 min.
Advantageously, the process of the present invention can be applied to an inclusion complex of cyclodextrin(s) or cyclodextrin derivative(s) (active agent complexed by cyclodextrin or a cyclodextrin derivative). A polymer obtained from an inclusion complex offers a better guarantee of cyclodextrin complexing properties; the presence of a complexing agent retains accessibility to the cavity of the cyclodextrin.
Heating condenses the hydroxyl groups of the cyclodextrin or cyclodextrin derivatives with the carboxylic acid groups of the poly(carboxylic) acid. A covalent ester type bond is formed between a cyclodextrin molecule or a cyclodextrin derivative molecule and a poly(carboxylic) acid molecule. When only two hydroxyl groups on each cyclodextrin molecule react with two distinct poly(carboxylic) acid molecules, a linear copolymer is formed. On the other hand, when three or more hydroxyl groups of the cyclodextrin form ester bonds with three or more distinct poly(carboxylic) acid molecules, a branched and/or cross-linked copolymer is formed. When the concatenation of molecules of cyclodextrin(s) and/or cyclodextrin derivative(s) molecules is more straight or slightly branched and has a low molar mass, the copolymer formed by that concatenation is soluble. When the chains form a three-dimensional network with a high molar mass, the copolymer obtained is insoluble.